Certain Neurons within the brain exhibit selective vulnerabilities to stresses related to normal aging and to specific neuropathologies. The unsuccessful response to these stresses is neurodegeneration. This project investigates the relationship between such stressed and neurodegeneration to determine the cellular factors responsible for neuron vulnerability and to discover endogenous mechanisms to overcome it. For this project two complementary models are being investigated to understand the cellular biology of neurons stress and neurodegeneration Model #1 is an in vivo model that characterizes the normal physiological role of amyloid precursor protein (APP) in the compromised rat cortex and the neuropathological role of beta-amyloid peptide in the intact brain. Model #2 is an in vitro model that examines the role of heat shock proteins in protecting against the hyperphosphorylation of the microtubule associated protein, tau and consequent loss of neurites in neuronal PC12 cells.